Project Summary/Abstract The toll of spinal cord injury on people and society is substantial, and particularly so when hand function is impaired and independence lost. We use well defined spinal cord injury (SCI) models in nonhuman primates and rodents to delineate the responses of major ascending and descending tracts, that reorganize post-injury and that mediate the recovery of hand function. Our past work shows that spinal injuries that remove sensory input from the opposing digits, can cause an initial deficit in hand function, from which monkeys recover over weeks and months post-lesion. This recovery occurs despite the permanent loss of most of the original sensory innervation to the hand. We have shown that spared primary motor (M1) and somatosensory (S1) cortical subdivisions of the corticospinal tract (CST) sprout extensively and bilaterally beyond their normal terminal territory within the cord following a deafferentation injury, but only when the injury involves the central nervous system. Similar responses can be demonstrated in rats which indicates the response is robust and conserved across mammalian species. In this grant, we will address some major gaps that remain in our understanding of the recovery process. We will do this by determining what happens at the neuronal circuit level, at the periphery, and following a more clinically relevant lesion involving both sensory and motor components. Our main focus is on monkeys, where our findings are directly translational, and on sub-chronic and chronic time points following injury. These are times when patients are more accessible to intervention, and the chronic time point in particular is poorly understood. Our specific aims in summary are as follows: 1. What happens to the central neuronal circuitry following a deafferentation injury? Here we will target the major inputs to the spinal cord (from the hand and cortex) and their connections, to assess how they reorganize to mediate the recovery of hand function. 2. How do peripheral nerves and receptors compensate for lost innervation to support significant recovery of sensation in the hand? 3. How does the addition of a small motor component to our lesion model, alter the recovery process and underlying connections? The lesion models to be used are particularly well defined, and involve peripheral and central, as well as sensory and motor components, which makes them clinically relevant. We use behavioral, electrophysiological, and a range of neuroanatomical techniques (including high resolution confocal microscopy), as well as powerful multifactorial statistical modeling to assess changes. Our findings will improve our understanding of the changes that occur in clinical injuries, and better enable the future development of effective treatments for people with spinal cord injury. Findings will be set in a broader context of behavioral recovery and system wide neuronal responses.